Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

GEFOS Consortium

doi:10.1371/journal.pone.0144531

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

GEFOS Consortium

Twin Research & Genetic Epidemiology

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Original language	English
Article number	e0144531
Journal	PLoS ONE
Volume	10
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0144531
Publication status	Published - 1 Dec 2015

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10.1371/journal.pone.0144531

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@article{495c9a74f70943f6bcca0bed314fd6ed,

title = "Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci",

abstract = "Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.",

author = "{GEFOS Consortium} and Sjur Reppe and Yunpeng Wang and Thompson, {Wesley K.} and McEvoy, {Linda K.} and Schork, {Andrew J.} and Verena Zuber and Marissa LeBlanc and Francesco Bettella and Mills, {Ian G.} and Desikan, {Rahul S.} and Srdjan Djurovic and Gautvik, {Kaare M.} and Dale, {Anders M.} and Andreassen, {Ole A.} and Karol Estrada and Unnur Styrkarsdottir and Evangelos Evangelou and Hsu, {Yi Hsiang} and Duncan, {Emma L.} and Ntzani, {Evangelia E.} and Ling Oei and Albagha, {Omar M.E.} and Najaf Amin and Kemp, {John P.} and Koller, {Daniel L.} and Guo Li and Liu, {Ching Ti} and Minster, {Ryan L.} and Alireza Moayyeri and Liesbeth Vandenput and Dana Willner and Xiao, {Su Mei} and Yerges-Armstrong, {Laura M.} and Zheng, {Hou Feng} and Nerea Alonso and Joel Eriksson and Kammerer, {Candace M.} and Kaptoge, {Stephen K.} and Leo, {Paul J.} and Gudmar Thorleifsson and Wilson, {Scott G.} and Wilson, {James F.} and Ville Aalto and Markku Alen and Aragaki, {Aaron K.} and Thor Aspelund and Elin Grundberg and Williams, {Frances M.K.} and Spector, {Timothy D.} and Brown, {Matthew A.}",

note = "Funding Information: This work was supported by the Research Council of Norway [grant number 183782/V50 to OAA]; the South East Norway Health Authority [grant number 2010-074 to OAA and 52009/8029 to KMG]; the National Institutes of Health [grant number T32 EB005970 to RSD, RC2DA029475 and R01HD061414 to AJS]; the Robert J. Glushko and Pamela Samuelson Graduate Fellowship to AJS; the 6th EU framework program [grant number LSHM-CT- 2003-502941 to KMG and SR]; and Oslo University Hospital, Ullevaal [grant number 52009/8029 to KMG]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank the genome-wide association study consortia for access to summary statistics data. Andreassen and Dale had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Membership of the GEFOS Consortium of Erasmus MC University Medical Center, Rotterdam, Netherlands: GEFOS lead author: Fernando Rivadeneira ([email protected]). Publisher Copyright: {\textcopyright} 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2015",

month = dec,

day = "1",

doi = "10.1371/journal.pone.0144531",

language = "English",

volume = "10",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "12",

}

TY - JOUR

T1 - Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

AU - GEFOS Consortium

AU - Reppe, Sjur

AU - Wang, Yunpeng

AU - Thompson, Wesley K.

AU - McEvoy, Linda K.

AU - Schork, Andrew J.

AU - Zuber, Verena

AU - LeBlanc, Marissa

AU - Bettella, Francesco

AU - Mills, Ian G.

AU - Desikan, Rahul S.

AU - Djurovic, Srdjan

AU - Gautvik, Kaare M.

AU - Dale, Anders M.

AU - Andreassen, Ole A.

AU - Estrada, Karol

AU - Styrkarsdottir, Unnur

AU - Evangelou, Evangelos

AU - Hsu, Yi Hsiang

AU - Duncan, Emma L.

AU - Ntzani, Evangelia E.

AU - Oei, Ling

AU - Albagha, Omar M.E.

AU - Amin, Najaf

AU - Kemp, John P.

AU - Koller, Daniel L.

AU - Li, Guo

AU - Liu, Ching Ti

AU - Minster, Ryan L.

AU - Moayyeri, Alireza

AU - Vandenput, Liesbeth

AU - Willner, Dana

AU - Xiao, Su Mei

AU - Yerges-Armstrong, Laura M.

AU - Zheng, Hou Feng

AU - Alonso, Nerea

AU - Eriksson, Joel

AU - Kammerer, Candace M.

AU - Kaptoge, Stephen K.

AU - Leo, Paul J.

AU - Thorleifsson, Gudmar

AU - Wilson, Scott G.

AU - Wilson, James F.

AU - Aalto, Ville

AU - Alen, Markku

AU - Aragaki, Aaron K.

AU - Aspelund, Thor

AU - Grundberg, Elin

AU - Williams, Frances M.K.

AU - Spector, Timothy D.

AU - Brown, Matthew A.

N1 - Funding Information: This work was supported by the Research Council of Norway [grant number 183782/V50 to OAA]; the South East Norway Health Authority [grant number 2010-074 to OAA and 52009/8029 to KMG]; the National Institutes of Health [grant number T32 EB005970 to RSD, RC2DA029475 and R01HD061414 to AJS]; the Robert J. Glushko and Pamela Samuelson Graduate Fellowship to AJS; the 6th EU framework program [grant number LSHM-CT- 2003-502941 to KMG and SR]; and Oslo University Hospital, Ullevaal [grant number 52009/8029 to KMG]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank the genome-wide association study consortia for access to summary statistics data. Andreassen and Dale had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Membership of the GEFOS Consortium of Erasmus MC University Medical Center, Rotterdam, Netherlands: GEFOS lead author: Fernando Rivadeneira ([email protected]). Publisher Copyright: © 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

AB - Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

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U2 - 10.1371/journal.pone.0144531

DO - 10.1371/journal.pone.0144531

M3 - Article

C2 - 26695485

AN - SCOPUS:84958012773

SN - 1932-6203

VL - 10

JO - PLoS ONE

JF - PLoS ONE

IS - 12

M1 - e0144531

ER -

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

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